Role of The Circadian Clock in the Development and Treatment of Mood Disorders

Ut Southwestern Medical Center, Dallas TX

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Abstract

DESCRIPTION (provided by applicant): Nearly all individuals suffering from mood disorders have abnormalities in their sleep/wake and other daily rhythms. Furthermore, many of the successful treatments for these disorders have dramatic effects on circadian rhythms and this action correlates with patient improvement. However, it is uncertain whether the abnormal clock function that is widely reported in these individuals underlies the development of mood disorders, or if the disruptions in rhythms are a byproduct from other disrupted circuits. Moreover, the mechanism by which the circadian clock might regulate mood is currently unknown. Our data suggests that the genes that make up the circadian clock play a key role in the regulation of depression-like and manic-like behavior in mouse models. Furthermore, at least a portion of the behavioral responses associated with depression or mania appears to be regulated by circadian gene expression outside of the central pacemaker of the suprachiasmatic nucleus (SCN). We hypothesize that the central clock of the SCN affects peripheral clocks in reward and mood-related regions of the brain such as the ventral tegmental area (VTA). Indeed the core circadian clock genes are expressed there, and several genes known to play an important role in mood regulation have robust circadian rhythms in expression in this region. If this connection between the SCN and these regions becomes out of sync or disrupted, this could potentially lead to depressive or manic episodes. This proposal utilizes both a mouse model of depression and a mouse model of mania that we have recently described to explore the underling biology between the circadian clock and mood regulation. Furthermore, we will determine how the treatments for mania and depression affect behavioral and molecular rhythms, and if these changes are important for therapeutic efficacy. PUBLIC HEALTH RELEVANCE Depression and other mood disorders are among the most common forms of psychiatric illness. A strong association between disruptions in circadian rhythms and these disorders has been reported for many years. However, it is unclear whether underlying clock abnormalities are the cause of these disorders, or how disruptions in the circadian system could lead to changes in mood. Through these proposed experiments, we seek to understand this connection between circadian rhythms and mood disorders, and explore the potential mechanisms that underlie this association. These experiments could lead us to more targeted treatments for these devastating disorders in the future.